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Investigating the role of STAT3 in mouse and rat embryonic stem cell self-renewal and differentiation

INVESTIGATING THE ROLE OF STAT3 IN MOUSE AND RAT EMBRYONIC STEM CELL
SELF‐RENEWAL AND DIFFERENTIATION
by
Eric Nathaniel Schulze
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR, AND CELLULAR BIOLOGY)
August 2010
Copyright 2010 Eric Nathaniel Schulze

Pluripotent embryonic stem (‘ES’) cells are typically derived and maintained using inductive or inhibitory signals that are thought to behave in a binary ‘on/off’ manner. Mouse ES cells are maintained in an excess of leukemia inhibitory factor (LIF) and rat ES cells in a cocktail of inhibitors that block both GSK3β and MAPK signaling in a STAT3-independent manner. Here, we provide evidence that both mouse and rat ES cell self-renewal is conserved via a STAT3-dependent mechanism that treats STAT3 activation as fluid and dynamic. We observe that increased Klf4 expression enhances STAT3-mediated self-renewal in mouse ES cells but is not essential to prevent differentiation. As well, increased STAT3 activation and ERK1/2 inhibition synergistically enhance self-renewal. In all, we propose that the self-renewal mechanism is a nested metastable cell-state within naïve pluripotency, and that further refinements to the self-renewal mechanism will allow for direct inter-species comparisons and derivation of novel ES and induced pluripotent cell population.

INVESTIGATING THE ROLE OF STAT3 IN MOUSE AND RAT EMBRYONIC STEM CELL
SELF‐RENEWAL AND DIFFERENTIATION
by
Eric Nathaniel Schulze
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR, AND CELLULAR BIOLOGY)
August 2010
Copyright 2010 Eric Nathaniel Schulze